PROJECT SUMMARY/ABSTRACT Forest wildfires are a global occurrence that is projected to increase both in the U.S. and around the world as a consequence of changes in temperature and precipitation patterns from global climate change. Exposure to airborne particulates in the form of wood smoke PM2.5 is strongly associated with an increase in the incidence of childhood asthma and associated morbidity. Allergic asthma typically has its origins in early life and is characterized by type 2 lung inflammation, airway hyperreactivity, mucus hypersecretion and tissue remodeling. It is becoming increasingly evident that prenatal exposure to air pollution plays a significant role in predisposing the offspring to the development of allergic disease, but the critical events responsible for disease inception are poorly understood. Using a model of wood smoke (WS) exposure, our preliminary data reveal that in utero exposure of C57BL/6 mice to WS resulted in offspring which displayed a pronounced increase in airway inflammation elicited by inhalation of house dust mite (HDM) allergen. Recent work in our laboratory and others strongly suggests that natural killer (NK) cells play a crucial role in the resolution of allergic airway inflammation. In addition, our preliminary findings reveal that prenatal smoke exposure resulted in augmented allergic inflammatory responses that coincided with reduced numbers of pulmonary NK cells. In this proposal, we will test the overall hypothesis that prenatal WS exposure increases the risk of allergic airway disease development in the offspring as a consequence of impaired NK cell function. Resolution of the nature and timing of events that underpin WS-associated asthma exacerbations in mice and correlation with responses in human subjects will form a core area of investigation. To test the hypothesis, two specific aims are proposed: (i) Determine whether prenatal WS exposure increases the risk of allergic airway disease development in the offspring as a consequence of changes in pulmonary NK cell function. In these experiments the effect of in utero WS exposure on the properties of lung NK cells will be investigated and their role in suppressing allergic lung inflammation examined. (ii) Delineate whether prenatal WS exposure predisposes offspring to an exacerbated allergic inflammation by disrupting maternal IL-15 production that impacts NK cell maturation in the progeny. This will entail examining the role of maternal IL-15 expression in molding offspring lung mucosal NK cell development and allergic responses elicited by inhaled HDM allergen. The impact of WS exposure on the production of IL-15 and cytokines or biomarkers will also be explored in humans in a controlled setting. Completion of these aims will provide a valuable mechanistic insight as to how prenatal exposure to air pollution impacts pulmonary NK cells and promotes the development of an asthma phenotype that will help identify future prevention strategies and therapeutic targets.